Cardiovascular Manifestations of Hemochromatosis: A Review of Pathophysiology, Mechanisms, and Treatment Options.

Hemochromatosis is a genetic disorder characterized by excessive absorption and accumulation of iron in the body. It is one of the most common inherited disorders. The excess iron deposition can cause damage to various organs, including the liver, heart, pancreas, and joints. If left untreated, hemochromatosis can lead to serious complications such as cirrhosis, diabetes, heart failure, and increased risk of certain cancers. Iron overload in hemochromatosis significantly affects the cardiovascular system, leading to morbidity and mortality. This article reviews the current literature describing the pathogenesis and various cardiovascular manifestations of hemochromatosis, including dilated cardiomyopathy, conduction abnormalities, heart failure, cardiac fibrosis, myocardial infarction, and valvular heart disease. This article aims to provide a detailed understanding of the cardiovascular manifestations associated with hemochromatosis and their underlying mechanisms through a review of current literature in publicly available databases.

Back Up at the Pump? I Have a Gut Feeling About This: A Review of the Gastrointestinal Manifestations From Congestive Heart Failure.

Heart failure, which is a clinical syndrome characterized by the heart's inability to maintain adequate cardiac output, is known to affect various organ systems in the body due to its ischemic nature and activation of the systemic immune response, but the resultant complications specifically on the gastrointestinal tract and the liver are not well discussed and poorly understood. Gastrointestinal-related phenomena are common symptoms experienced in patients with heart failure and frequently found to increase morbidity and mortality in these populations. The relationship between the gastrointestinal tract and heart failure are strongly linked and influence each other much so that the bidirectional association of the two is oftentimes referred to as cardiointestinal syndrome. Manifestations include gastrointestinal prodrome, bacterial translocation and protein-losing gastroenteropathy by gut wall edema, cardiac cachexia, hepatic insult and injury, and ischemic colitis. More attention is needed from a cardiology perspective to recognize these common presenting gastrointestinal phenomena that affect much of our patient population with heart failure. In this overview, we describe the association between heart failure and the gastrointestinal tract, the pathophysiology, lab findings, clinical manifestations and complications, and the management involved.

The Critical Role of the Adipocytokine NOV in Obstructive Sleep Apnea Induced Cardiometabolic Dysfunction: A Review.

Obstructive sleep apnea (OSA) is highly prevalent and associated with oxidative stress, chronic inflammation, and adverse cardiovascular consequences. The comorbid condition of obesity remains epidemic. Both obesity and OSA are highly comorbid in patients with cardiovascular disease including atrial fibrillation, resistant hypertension, congestive heart failure, and coronary artery disease. Patients with these preexisting cardiovascular conditions should be screened for OSA with a low threshold to treat, even if OSA severity is mild. Nephroblastoma overexpressed (NOV/CCN3) protein has been identified in multiple chronic inflammatory states, most notably in obesity and more recently in OSA, even in the absence of obesity. As such, NOV may represent an important biomarker for oxidative stress in OSA and may lead to a deeper understanding of the relationship between OSA and its clinical sequelae.

Silencing the Adipocytokine NOV: A Novel Approach to Reversing Oxidative Stress-Induced Cardiometabolic Dysfunction.

OBJECTIVE: NOV/CCN3 is an adipocytokine recently linked to obesity, insulin resistance, and cardiometabolic dysfunction. NOV is manufactured and secreted from adipose tissue, with blood levels highly correlated with BMI. NOV levels are increased in obesity and a myriad of inflammatory diseases. Elevated NOV levels cause oxidative stress by increasing free radicals, decreasing antioxidants, and decreasing heme oxygenase (HO-1) levels, resulting in decreased vascular function. Silencing NOV in NOV knockout mice improved insulin sensitivity. We wanted to study how suppressing NOV expression in an obese animal model affected pathways and processes related to obesity, inflammation, and cardiometabolic function. This is the first study to investigate the interaction of adipose tissue-specific NOV/CCN3 and cardiometabolic function. METHODS: We constructed a lentivirus containing the adiponectin-promoter-driven shNOV to examine the effect of NOV inhibition (shNOV) in adipose tissue on the heart of mice fed a high-fat diet. Mice were randomly divided into three groups (five per group): (1) lean (normal diet), (2) high-fat diet (HFD)+ sham virus, and (3) HFD + shNOV lentivirus. Blood pressure, tissue inflammation, and oxygen consumption were measured. Metabolic and mitochondrial markers were studied in fat and heart tissues. RESULTS: Mice fed an HFD developed adipocyte hypertrophy, fibrosis, inflammation, and decreased mitochondrial respiration. Inhibiting NOV expression in the adipose tissue of obese mice by shNOV increased mitochondrial markers for biogenesis (PGC-1α, the nuclear co-activator of HO-1) and functional integrity (FIS1) and insulin signaling (AKT). The upregulation of metabolic and mitochondrial markers was also evident in the hearts of the shNOV mice with the activation of mitophagy. Using RNA arrays, we identified a subgroup of genes that highly correlated with increased adipocyte mitochondrial autophagy in shNOV-treated mice. A heat map analysis in obese mice confirmed that the suppression of NOV overrides the genetic susceptibility of adiposity and the associated detrimental metabolic changes and correlates with the restoration of anti-inflammatory, thermogenic, and mitochondrial genes. CONCLUSION: Our novel findings demonstrate that inhibiting NOV expression improves adipose tissue function in a positive way in cardiometabolic function by inducing mitophagy and improving mitochondrial function by the upregulation of PGC-1α, the insulin sensitivity signaling protein. Inhibiting NOV expression increases PGC-1, a key component of cardiac bioenergetics, as well as key signaling components of metabolic change, resulting in improved glucose tolerance, improved mitochondrial function, and decreased inflammation. These metabolic changes resulted in increased oxygen consumption, decreased adipocyte size, and improved cardiac metabolism and vascular function at the structural level. The crosstalk of the adipose tissue-specific deletion of NOV/CCN3 improved cardiovascular function, representing a novel therapeutic strategy for obesity-related cardiometabolic dysfunction.

Cancer and cardiovascular-related perceived risk in a diverse cancer center catchment area.

PURPOSE: Despite cancer and cardiovascular disease (CVD) sharing several modifiable risk factors, few unified prevention efforts exist. We sought to determine the association between risk perception for cancer and CVD and engagement in healthy behaviors. METHODS: Between May 2019 and August 2020, we conducted a cross-sectional survey of adults ≥ 40 years residing in Brooklyn neighborhoods with high cancer mortality. We considered one's perceived risk of cancer and CVD compared to age counterparts as the primary exposures. The primary study outcome was a weighted health behavior score (wHBS) composed of 5 domains: physical activity, no obesity, no smoking, low alcohol intake, and healthy diet. Modified Poisson regression models with robust error variance were used to assess associations between perceived risk for cancer and CVD and the wHBS, separately. RESULTS: We surveyed 2448 adults (mean [SD] age, 61.4 [12.9] years); 61% female, 30% Non-Hispanic White, and 70% racial/ethnic minorities. Compared to their age counterparts nearly one-third of participants perceived themselves to be at higher CVD or cancer risk. Perceiving higher CVD risk was associated with an 8% lower likelihood of engaging in healthy behaviors (RR 0.92; 95% CI 0.86-0.99). Perceiving greater cancer risk was associated with a 14% lower likelihood of engaging in healthy behaviors (RR 0.86; 95% CI 0.79-0.95). The association between cancer risk and wHBS attenuated but remained significant (aRR 0.90; 95% CI 0.82-0.98) after adjustment. CONCLUSION: Identifying high-risk subgroups and intervening on shared risk behaviors could have the greatest long-term impact on reducing CVD and cancer morbidity and mortality.

The Association of Nephroblastoma Overexpressed (NOV) and Endothelial Progenitor Cells with Oxidative Stress in Obstructive Sleep Apnea.

OBJECTIVE: Obstructive sleep apnea (OSA) is a sleep disorder characterized by intermittent hypoxia, chronic inflammation, and oxidative stress and is associated with cardiometabolic disease. Several biological substrates have been associated with OSA such as nephroblastoma overexpressed (NOV), endothelial progenitor cells (EPC), and circulating endothelial cells (CEC). Few studies have looked at the association of NOV with OSA while the EPC/CEC relationships with OSA are unclear. In this study, we hypothesize that (1) NOV is associated with the severity of OSA independent of BMI, identifying a protein that may play a role in the biogenesis of OSA complications, and (2) EPCs and CECs are also associated with the severity of OSA and are biomarkers of endothelial dysfunction in OSA. METHODS: 61 subjects underwent overnight polysomnography (PSG), clinical evaluation, and blood analysis for NOV, EPC, CEC, interleukin 6 (IL-6), and other potential biomarkers. RESULTS: NOV and EPCs were independently associated with the oxygen desaturation index (ODI) after adjusting for potential confounders including body mass index (BMI), age, and sex (NOV p = 0.032; EPC p = 0.001). EPC was also independently associated with AHI after adjusting for BMI, age, and sex (p = 0.017). IL-6 was independently associated with AHI, but not with ODI. CONCLUSION: NOV and EPC levels correlate with the degree of OSA independent of BMI, indicating that these biomarkers could potentially further elucidate the relationship between OSA patients and their risk of the subsequent development of cardiovascular disease.

Cold Press Pomegranate Seed Oil Attenuates Dietary-Obesity Induced Hepatic Steatosis and Fibrosis through Antioxidant and Mitochondrial Pathways in Obese Mice.

AIM: Obesity is associated with metabolic syndrome, hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes. In this study, we investigated whether the dietary supplementation of pomegranate seed oil (PSO) exerted a protective effect on liver lipid uptake, fibrosis, and mitochondrial function in a mouse model of obesity and insulin resistance. METHOD: In this in vivo study, eight-week-old C57BL/6J male mice were fed with a high fat diet (HFD) for 24 weeks and then were divided into three groups as follows: group (1) Lean; group (n = 6) (2) HF diet; group (n = 6) (3) HF diet treated with PSO (40 mL/kg food) (n = 6) for eight additional weeks starting at 24 weeks. Physiological parameters, lipid droplet accumulation, inflammatory biomarkers, antioxidant biomarkers, mitochondrial biogenesis, insulin sensitivity, and hepatic fibrosis were determined to examine whether PSO intervention prevents obesity-associated metabolic syndrome. RESULTS: The PSO group displayed an increase in oxygen consumption, as well as a decrease in fasting glucose and blood pressure (p < 0.05) when compared to the HFD-fed mice group. PSO increased both the activity and expression of hepatic HO-1, downregulated inflammatory adipokines, and decreased hepatic fibrosis. PSO increased the levels of thermogenic genes, mitochondrial signaling, and lipid metabolism through increases in Mfn2, OPA-1, PRDM 16, and PGC1α. Furthermore, PSO upregulated obesity-mediated hepatic insulin receptor phosphorylation Tyr-972, p-IRB tyr1146, and pAMPK, thereby decreasing insulin resistance. CONCLUSIONS: These results indicated that PSO decreased obesity-mediated insulin resistance and the progression of hepatic fibrosis through an improved liver signaling, as manifested by increased insulin receptor phosphorylation and thermogenic genes. Furthermore, our findings indicate a potential therapeutic role for PSO in the prevention of obesity-associated NAFLD, NASH, and other metabolic disorders.

Cold-Pressed Nigella Sativa Oil Standardized to 3% Thymoquinone Potentiates Omega-3 Protection against Obesity-Induced Oxidative Stress, Inflammation, and Markers of Insulin Resistance Accompanied with Conversion of White to Beige Fat in Mice.

Excessive lipid accumulation in white adipose tissue (WAT) results in adipocyte hypertrophy and chronic low-grade inflammation, which is the major cause of obesity-associated insulin resistance and consequent metabolic disease. The development of beige adipocytes in WAT (browning of WAT) increases energy expenditure and has been considered as a novel strategy to counteract obesity. Thymoquinone (TQ) is the main bioactive quinone derived from the plant Nigella Sativa and has antioxidative and anti-inflammatory capacities. Fish oil omega 3 (ω3) enhances both insulin sensitivity and glucose homeostasis in obesity, but the involved mechanisms remain unclear. The aim of this study is to explore the effects of TQ and ω3 PUFAs (polyunsaturated fatty acids) on obesity-associated inflammation, markers of insulin resistance, and the metabolic effects of adipose tissue browning. 3T3-L1 cells were cultured to investigate the effects of TQ and ω3 on the browning of WAT. C57BL/6J mice were fed a high-fat diet (HFD), supplemented with 0.75% TQ, and 2% ω3 in combination for eight weeks. In 3T3-L1 cells, TQ and ω3 reduced lipid droplet size and increased hallmarks of beige adipocytes such as uncoupling protein-1 (UCP1), PR domain containing 16 (PRDM16), fibroblast growth factor 21 (FGF21), Sirtuin 1 (Sirt1), Mitofusion 2 (Mfn2), and heme oxygenase 1 (HO-1) protein expression, as well as increased the phosphorylation of Protein Kinase B (AKT) and insulin receptors. In the adipose tissue of HFD mice, TQ and ω3 treatment attenuated levels of inflammatory adipokines, Nephroblastoma Overexpressed (NOV/CCN3) and Twist related protein 2 (TWIST2), and diminished adipocyte hypoxia by decreasing HIF1α expression and hallmarks of beige adipocytes such as UCP1, PRDM16, FGF21, and mitochondrial biogenesis markers Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), Sirt1, and Mfn2. Increased 5' adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation and HO-1 expression were observed in adipose with TQ and ω3 treatment, which led to increased pAKT and pIRS1 Ser307 expression. In addition to the adipose, TQ and ω3 also increased inflammation and markers of insulin sensitivity in the liver, as demonstrated by increased phosphorylated insulin receptor (pIR tyr972), insulin receptor beta (IRß), UCP1, and pIRS1 Ser307 and reduced NOV/CCN3 expression. Our data demonstrate the enhanced browning of WAT from TQ treatment in combination with ω3, which may play an important role in decreasing obesity-associated insulin resistance and in reducing the chronic inflammatory state of obesity.

Racial Disparities with Esophageal Cancer Mortality at a High-Volume University Affiliated Center: An All ACCESS Invitation.

BACKGROUND: Esophageal cancer (EC) has a dismal prognosis with 5-year survival < 19%. Black patients with EC have higher mortality than white patients, but the cause of this disparity is unclear. We sought to investigate the impact of race upon overall mortality (OM) among EC patients at our institution. METHODS: We performed a single-center retrospective review of all patients diagnosed with EC between January 2010 through December 2016 with follow-up through October 2017. We compared the difference among categorical variables and mortality using Fisher's exact test. Odds ratios (OR) and hazard regression (HR) were constructed to analyze treatment options by race. The Kaplan-Meier method was used to plot OM curves by race. We also used a logistic regression analysis to construct a predictive model for mortality based on histology and race. RESULTS: We identified 77 patients (62% male) diagnosed with EC. There was no difference in treatments offered based on race. After adjusting for age, histology and stage, we found mortality was significantly higher in blacks when compared to whites (HR 14.07, 95% CI [2.33-129.70] p < 0.008). Our predictive model revealed that blacks had a higher probability of mortality at all stages of EC. CONCLUSIONS: We found race to be an independent risk factor for OM in EC patients. This likely reflects differences in healthcare utilization or access, as evidenced by higher prevalence of Stage IV EC in black patients. Continued investigation is needed to address this disparity locally and nationally.

The association of NOV/CCN3 with obstructive sleep apnea (OSA): preliminary evidence of a novel biomarker in OSA.

Obstructive sleep apnea (OSA) has a strong association with cardiovascular and metabolic abnormalities, although the mechanism driving this association is not well established. NOV/CCN3, a multifunctional extracellular matrix protein, may play a mechanistic and/or prognostic role in these associations. We hypothesized that patients with OSA, which primarily affects obese individuals, will have increased levels of NOV, and that NOV can serve as a biomarker in patients to predict OSA as well as metabolic and cardiac risk. Ten morbidly obese and 10 healthy lean subjects underwent overnight polysomnography (PSG) and clinical evaluation. Blood samples were analyzed for NOV levels, adiponectin and IL-6. OSA was found in nine obese subjects and three lean subjects. NOV levels were significantly higher in the OSA vs. no OSA group (2.1 ± 0.9 vs. 1.3 ± 0.8, p < 0.03). NOV levels were significantly higher in the obese vs. lean group (2.2 ± 0.3 vs. 1.4 ± 0.2-fold change, p < 0.03). Among lean subjects, NOV levels were significantly higher in the OSA vs. no OSA group (2.1 ± 0.9 vs. 1.0 ± 0.4, p < 0.05). NOV and AHI were positively correlated (ρ = 0.49, p = 0.033). IL-6 and adiponectin differences in obese vs. lean and OSA vs. no OSA were consistent with an inflammatory phenotype in obese subjects and OSA subjects. NOV is a novel biomarker of the presence and severity of OSA and a potential marker of future cardiovascular and metabolic disease in OSA patients.

Oxidized HDL is a potent inducer of adipogenesis and causes activation of the Ang-II and 20-HETE systems in human obese females.

BACKGROUND: Oxidized-HDL (OX-HDL) has been reported to increase coronary events in obese patients; however, OX-HDL has not been studied in subjects with the metabolic syndrome. A high body mass index (BMI) correlates positively with higher levels of metabolic syndrome biomarkers including vasoconstrictors and adipokines. We hypothesize that a subject with a high BMI would present with higher levels of OX-HDL, 20-HETE and Angiotensin II (Ang II) with a reciprocal reduction in serum adiponectin. METHODS: Female subjects with a BMI of 17-25 and a BMI of 30-40, without overt cardiovascular disease, were enrolled in the study. All patients had a history and physical exam documenting the absence of signs and symptoms of cardiovascular disease. Appropriate screening was done and documented. Blood pressure was taken at two discrete points. The BP data are presented as the average. Changes in the relationship between BMI, OX-HDL, 20-HETE, Ang II, TNFα, isoprostane and adiponectin were examined. In addition, the effects of OX-HDL, 20-HETE and Ang II on adipogenesis were examined in human MSC derived adipocytes. RESULTS: Subjects with a high BMI>30 displayed an increase in OX-HDL and isoprostane (P<0.05) compared to those with the lower BMI<25 which was associated with an increase in Ang II and 20-HETE (p<0.05). Serum TNFα levels increased in subjects with a high BMI, compared to subjects with the lower BMI (p<0.05). In contrast, adiponectin levels were increased in subjects with a low BMI compared to obese subjects (p<0.05). In MSC derived adipocytes OX-HDL increased adipogenesis 6 fold at a concentration of 50ng compared to untreated adipocytes. Adipocytes treated with Ang II and 20-HETE also displayed increased adipogenesis (p<0.05), which was attenuated by endogenous increases of the anti-oxidant heme oxygenase-1. Our study demonstrates that OX-HDL presents a unique inflammatory biomarker profile in obese females with the metabolic syndrome at risk for developing cardiovascular disease. CONCLUSIONS: Females with increased BMI (30-40) exhibit a marked increase in OX-HDL and isoprostane levels, which was associated with an increase in 20-HETE, TNF α and Ang II and decreased levels of adiponectin when compared to a group with a low BMI. OX-HDL had a more powerful adipogenic effect when compared to 20-HETE and Ang II. Our study demonstrates that OX-HDL presents a unique inflammatory biomarker profile in obese females with the metabolic syndrome at risk for developing cardiovascular disease. This represents a novel mechanism by which females with a high BMI and controlled blood pressure remain "at risk" for the development of the metabolic syndrome as a result of increased adipogenesis by OX-HDL and activation of the 20-HETE and Ang II systems.

Predictors of in-hospital mortality and acute myocardial infarction in thrombotic thrombocytopenic purpura.

BACKGROUND: Despite the widespread availability of plasmapheresis as a therapy, thrombotic thrombocytopenic purpura is associated with significant morbidity and mortality. There is a paucity of data on the predictors of poor clinical outcome in this population. Acute myocardial infarction is a recognized complication of thrombotic thrombocytopenic purpura. Little is known about the magnitude of this problem, its risk factors, and its influence on mortality in patients hospitalized with thrombotic thrombocytopenic purpura. METHODS: We used the 2001-2010 Nationwide Inpatient Sample database to identify patients aged ≥18 years with the diagnosis of thrombotic thrombocytopenic purpura (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] code 446.6) who also received therapeutic plasmapheresis (ICD-9-CM code 99.71) during the hospitalization. Patients with acute myocardial infarction were identified using the Healthcare Cost and Utilization Project Clinical Classification Software code 100. Stepwise logistic regression was used to determine independent predictors of in-hospital mortality and acute myocardial infarction in thrombotic thrombocytopenic purpura patients. RESULTS: Among the 4032 patients (mean age 47.5 years, 67.7% women, and 36.9% white) with thrombotic thrombocytopenic purpura who also underwent plasmapheresis, in-hospital mortality was 11.1%. Independent predictors of increased in-hospital mortality were older age (odds ratio [OR] 1.03; 95% confidence interval [CI], 1.02-1.04; P <.001), acute myocardial infarction (OR 1.89; 95% CI, 1.24-2.88; P = .003), acute renal failure (OR 2.75; 95% CI, 2.11-3.58; P <.001), congestive heart failure (OR 1.66; 95% CI, 1.17-2.34; P = .004), acute cerebrovascular disease (OR 2.68; 95% CI, 1.87-3.85; P <.001), cancer (OR 2.49; 95% CI, 1.83-3.40; P <.001), and sepsis (OR 2.59; 95% CI, 1.88-3.59; P <.001). Independent predictors of acute myocardial infarction were older age (OR 1.03; 95% CI, 1.02-1.04; P <.001), smoking (OR 1.60; 95% CI, 1.14-2.24; P = .007), known coronary artery disease (OR 2.59; 95% CI, 1.76-3.81; P <.001), and congestive heart failure (OR 2.40; 95% CI, 1.71-3.37; P <.001). CONCLUSION: In this large national database, patients with thrombotic thrombocytopenic purpura had an in-hospital mortality rate of 11.1% and an acute myocardial infarction rate of 5.7%. Predictors of in-hospital mortality were older age, acute myocardial infarction, acute renal failure, congestive heart failure, acute cerebrovascular disease, cancer, and sepsis. Predictors of acute myocardial infarction were older age, smoking, known coronary artery disease, and congestive heart failure.

HO-1 induction improves the type-1 cardiorenal syndrome in mice with impaired angiotensin II-induced lymphocyte activation.

Type-1 cardiorenal syndrome, characterized by acute kidney dysfunction secondary to cardiac failure and renal arteriolar vasoconstriction, is mediated by the renin-angiotensin-aldosterone axis and sympathetic nervous system activation. Previous reports indicate that angiotensin II modulates immune function and causes recruitment and activation of T-lymphocytes. The goal of this study was to evaluate the effects of postischemic heart failure on renal morphology and circulation and the beneficial effects of heme oxygenase-1 (HO-1) induction in T-lymphocyte-suppressed severe combined immune deficiency (SCID) mice. Mice were divided into 4 groups: sham, myocardial infarction (MI), MI treated with an HO-1 inducer, cobalt protoporphyrin, and with or without stannous mesoporphyrin, an inhibitor of HO activity. Heart and kidney function were studied 30 days after surgery. Fractional area change was reduced 30 days after surgery in both the C57 and SCID MI-groups as compared with their respective controls (P<0.01). Renal Pulsatility Index and renal injury were increased in C57 and SCID MI-groups compared with the sham group. HO-1 induction improved renal vasoconstriction as well as ameliorated renal injury in both the SCID and C57 MI-groups (P<0.01). However, improvement was more evident in SCID mice. In addition, our results showed that plasma creatinine, angiotensin II, and renin were significantly increased in the C57 and SCID MI-groups as compared with their respective controls. HO-1 induction decreased these parameters in both MI groups. Stannous mesoporphyrin reversed the beneficial effect of cobalt protoporphyrin in both mouse strains. The study demonstrates that T-lymphocyte suppression facilitated the HO-1-dependent improvement in the attenuation of type-1 cardiorenal syndrome.

Increased heme-oxygenase 1 expression in mesenchymal stem cell-derived adipocytes decreases differentiation and lipid accumulation via upregulation of the canonical Wnt signaling cascade.

INTRODUCTION: Heme oxygenase (HO), a major cytoprotective enzyme, attenuates oxidative stress and obesity. The canonical Wnt signaling cascade plays a pivotal role in the regulation of adipogenesis. The present study examined the interplay between HO-1and the Wnt canonical pathway in the modulation of adipogenesis in mesenchymal stem cell (MSC)-derived adipocytes. METHODS: To verify the role of HO-1 in generating small healthy adipocytes, cobalt protoporphyrin (CoPP), inducer of HO-1, was used during adipocyte differentiation. Lipid accumulation was measured by Oil red O staining and lipid droplet size was measured by BODIPY staining. RESULTS: During adipogenesis in vitro, differentiating pre-adipocytes display transient increases in the expression of genes involved in canonical Wnt signaling cascade. Increased levels of HO-1 expression and HO activity resulted in elevated levels of ß-catenin, pGSK3ß, Wnt10b, Pref-1, and shh along with increased levels of adiponectin (P < 0.05). In addition, induction of HO-1 resulted in a reduction in C/EBPα, PPARγ, Peg-1/Mest, aP2, CD36 expression and lipid accumulation (P < 0.05). Suppression of HO-1 gene by siRNA decreased Wnt10b, pGSK3ß and ß-catenin expression, and increased lipid accumulation. The canonical Wnt responsive genes, IL-8 and SFRP1, were upregulated by CoPP and their expression was decreased by the concurrent administration of tin mesoporphyrin (SnMP), an inhibitor of HO activity. Furthermore, knockdown of Wnt10b gene expression by using siRNA showed increased lipid accumulation, and this effect was not decreased by concurrent treatment with CoPP. Also our results show that blocking the Wnt 10b antagonist, Dickkopf 1 (Dkk-1), by siRNA decreased lipid accumulation and this effect was further enhanced by concurrent administration of CoPP. CONCLUSIONS: This is the first study to demonstrate that HO-1 acts upstream of canonical Wnt signaling cascade and decreases lipogenesis and adipocyte differentiation suggesting that the HO-1 mediated increase in Wnt10b can modulate the adipocyte phenotype by regulating the transcriptional factors that play a role in adipogenesis. This is evidenced by a decrease in lipid accumulation and inflammatory cytokine levels, increased adiponectin levels and elevation of the expression of genes of the canonical Wnt signaling cascade.

Predictors of mortality, rehospitalization for syncope, and cardiac syncope in 352 consecutive elderly patients with syncope.

OBJECTIVES: To investigate the etiologies of syncope and predictors of all-cause mortality, rehospitalization, and cardiac syncope in consecutive elderly patients presenting with syncope to our emergency department. PARTICIPANTS: Participants were 352 consecutive patients aged 65 years or older with syncope admitted to hospital from the emergency department. DESIGN: Observational retrospective study. MEASUREMENTS: Review of medical records for history, physical examination, medications, and tests to determine causes of syncope. Cox stepwise logistic regression analysis was performed to identify significant independent prognostic factors for rehospitalization with syncope, all-cause mortality, and cardiac syncope. RESULTS: Of 352 patients, mean age 78 years, the etiology of syncope was diagnosed in 243 patients (69%). Vasovagal syncope was diagnosed in 12%, volume depletion in 14%, orthostatic hypotension in 5%, cardiac syncope in 29%, carotid sinus hypersensitivity in 2%, and drug overdose/others in 7% of patients. During a mean follow-up of 24 months, 10 patients (3%) were readmitted to the hospital for syncope and 39 (11%) died. Stepwise logistic regression analysis identified history of congestive heart failure (OR 5.18; 95% CI 1.23-21.84, P = .0257) and acute coronary syndrome (OR 5.95; 95% CI 1.11-31.79, P = .037) as independent risk factors for rehospitalization. Significant independent prognostic factors for mortality were diabetes mellitus (OR 2.08; 95% CI 1.09-3.99, P = .0263), history of smoking (OR 2.23; 95% CI 1.10-4.49, P = .0255), and use of statins (OR 0.37; 95% CI 0.19-0.72, P = .0036). Independent risk factors for predicting a cardiac cause of syncope were an abnormal electrocardiogram (OR 2.58; 95% CI 1.46-4.57, P = .0012) and reduced ejection fraction (OR 2.92; 95% CI 1.70-5.02, P < .001). The San Francisco Syncope Rule and Osservatorio Epidemiologico sulla Sincope nel Lazio scores did not predict mortality or rehospitalization in our study population. CONCLUSIONS: Significant independent risk factors for rehospitalization for syncope were congestive heart failure and acute coronary syndrome. Significant independent risk factors for mortality were diabetes mellitus, history of smoking, and use of statins (inverse association).

Association of corrected QT interval with long-term mortality in patients with syncope.

INTRODUCTION: The electrocardiographic parameters QRS duration, QRS-T angle and QTc can predict mortality in patients with cardiovascular disease. The prgnostic value of these parameters in hospitalized patients with syncope needs investigation. MATERIAL AND METHODS: We retrospectively studied 590 consecutive patients hospitalized with syncope. After excluding patients with baseline abnormal rhythm, QT- prolonging medications, and missing data, 459 patients were analyzed. Baseline demographic characteristics, co-morbidities, medication use, San Francisco Syncope Rule (SFSR) and Osservatorio Epidemiologico sulla Sincope nel Lazio (OESIL) score and data on mortality were collected. The categorical variables and continuous variables of the 2 groups of patients with prolonged QTc and normal QTc interval were analyzed by Fischer's exact test and Mann-Whitney Test. A stepwise Cox regression model was used for time to death analysis. RESULTS: Of 459 patients, prolonged QTc interval was observed in 122 (27%). Mean follow-up was 41 months. Patients with prolonged QTc interval had higher prevalence of cardiovascular disease, OESIL score, high risk SFSR, hypertension, dyslipidemia, coronary artery disease, congestive heart failure, and increased mortality. Stepwise Cox regression analysis showed that significant independent prognostic factors for time to death were prolonged QTc interval (p = 0.005), age (p = 0.001), diabetes mellitus (p = 0.001) and history of malignancy (p = 0.006). QRS duration and QRS-T angle were not independent predictors of mortality. CONCLUSIONS: A prolonged QTc interval is an independent predictor of long-term mortality in hospitalized patients with syncope.

Peroxisome proliferator-activated receptor delta agonist attenuates nicotine suppression effect on human mesenchymal stem cell-derived osteogenesis and involves increased expression of heme oxygenase-1.

Smoking has long been associated with osteoporosis, decreased bone mineral density, increased risk of bone fracture, and increased health costs. Nicotine, the main component of cigarette smoke, has major negative effects on bone metabolism and skeletal remodeling in vivo. Although osteoblasts and osteoblast-like cells have been used extensively to study the impact of nicotine, few studies have been performed on human mesenchymal stem cells (hMSCs). In this context, we examined the impact of nicotine on (a) hMSCs proliferation, (b) osteoblastic differentiation, (c) alkaline phosphatase (ALP) activity, and (d) expression of canonical genes during differentiation of hMSCs. MSCs isolated from human bone marrow were treated with different concentrations (0, 0.1, 1 and 10 µM) of nicotine for 7 days. Nicotine caused a dose-dependent decrease in cell proliferation, decreased heme oxygenase-1 (HO-1) expression (p < 0.05) and attenuated osteogenesis (p < 0.05) in hMSCs (45 % reduction at day 14). In addition, nicotine caused a dose-dependent decrease in alizarin red staining for calcium and staining for ALP. Induction of HO-1 by peroxisome proliferator-activated receptor delta agonist (GW0742) prevented the effect of nicotine. Nicotine caused a dose-dependent reduction in the expression of BMP-2, a well-known marker for bone formation; however, this was prevented by GW0742 treatment. Therefore, induction of HO-1 prevents the deleterious effects of nicotine on osteogenesis in hMSC. This offers insight into both how nicotine affects bone remodeling and a therapeutic approach to prevent fracture and osteoporosis in smokers.

Heme oxygenase gene targeting to adipocytes attenuates adiposity and vascular dysfunction in mice fed a high-fat diet.

We examined the hypothesis that adipocyte dysfunction in mice fed a high-fat (HF) diet can be prevented by lentiviral-mediated and adipocyte specific-targeting delivery of the human heme oxygenase-1 (aP2-HO-1). A bolus intracardial injection of aP2-HO-1 resulted in expression of human HO-1 for up to 9.5 months. Transduction of aP2-HO-1 increased human HO-1 expression in fat tissues without affecting murine HO-1. In mice fed a HF diet, aP2-HO-1 transduction attenuated the increases in body weight, blood glucose, blood pressure, and inflammatory cytokines, as well as the content of both visceral and subcutaneous fat. Transduction of aP2-HO-1 increased the numbers of adipocytes of small cell size (P<0.05), insulin sensitivity (P<0.05), adiponectin levels, as well as vascular relaxation to acetylcholine compared with HF mice administered the aP2-green fluorescent protein. Adipocytes of mice fed a HF diet expressed high levels of peroxisome proliferator activator receptor, aP2, C/EBP, and Wnt5b proteins and displayed marked increases in Peg1/Mesoderm specific transcript (P<0.03). Transduction of aP2-HO-1 lowered the elevated levels of these proteins and increased Sonic hedgehog, Wnt10b, and ß-catenin (P<0.05). Inhibition of HO activity by administration of tin mesoporphyrin to HF-fed mice transduced with the aP2-HO-1 reversed the decrease in Peg1/Mesoderm-specific transcript, TNFα, and MCP-1 levels. Collectively, this novel study demonstrates that adipocyte-specific overexpression of HO-1 attenuates HF-mediated adiposity and vascular dysfunction; increases insulin sensitivity; and improves adipocyte function by increasing adiponectin, Shh, and WNT10b, and by decreasing inflammatory cytokines. These effects are reversed by the HO activity inhibitor, stannous mesoporphyrin.

Association of warfarin use with valvular and vascular calcification: a review.

Vitamin K is required for the activity of various biologically active proteins in our body. Apart from clotting factors, vitamin K-dependent proteins include regulatory proteins like protein C, protein S, protein Z, osteocalcin, growth arrest-specific gene 6 protein, and matrix Gla protein. Glutamic acid residues in matrix Gla protein are γ-carboxylated by vitamin K-dependent γ-carboxylase, which enables it to inhibit calcification. Warfarin, being a vitamin K antagonist, inhibits this process, and has been associated with calcification in various animal and human studies. Though no specific guidelines are currently available to prevent or treat this less-recognized side effect, discontinuing warfarin and using an alternative anticoagulant seems to be a reasonable option. Newer anticoagulants such as dabigatran and rivaroxaban offer promise as future therapeutic options in such cases. Drugs including statins, alendronate, osteoprotegerin, and vitamin K are currently under study as therapies to prevent or treat warfarin-associated calcification. Copyright © 2011 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose.

Etiology of syncope in patients hospitalized with syncope and predictors of mortality and rehospitalization for syncope at 27-month follow-up.

The authors investigated the etiologies of syncope and risk factors for mortality and rehospitalization for syncope at 27-month follow-up in 325 consecutive patients, mean age 66 years, hospitalized for syncope. The causes of syncope were diagnosed in 241 patients (74%). Of 325 patients, 13 (4%) were rehospitalized for syncope and 38 (12%) died. Stepwise logistic regression analysis showed that significant independent prognostic factors for rehospitalization for syncope were diabetes (odds ratio [OR], 5.7; 95% confidence interval [CI], 1.6-20.4), atrial fibrillation (OR, 4.0; 95% CI, 1.0-15.6), and smoking (OR, 4.6; 95% CI, 1.3-16.8). Stepwise Cox regression analysis showed that significant independent prognostic factors for time to mortality were diabetes (hazard ratio [HR], 2.7; 95% CI, 1.4-5.2), coronary artery bypass graft surgery (HR, 2.9; 95% CI, 1.3-6.5), malignancy history (HR, 2.5; 95% CI, 1.2-5.2), narcotics use (HR, 4.0; 95% CI, 1.7-9.8), smoking (HR, 2.8; 95% CI, 1.4-5.5), atrial fibrillation (HR, 2.4; 95% CI, 1.0-5.4), and volume depletion (HR, 2.8; 95% CI, 1.4-5.8). Copyright © 2011 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose.